Case Report Journal of Hematology & Multiple Myeloma Published: 24 Nov, 2016
Successful Management of Twin Pregnancy via In Vitro Fertilization in a Patient with Chronic Myeloid Leukemia
AlSaffar WA1, Abdulbaqi M2, Jatham A2 and Al-Anazi KA2* 1King Abdulaziz University, Saudi Arabia
2Department of Hematology and Hematopoietic Stem Cell Transplantation, King Fahad Specialist Hospital, Saudi Arabia
Abstract The diagnosis of leukemia during pregnancy is a rather uncommon event. Also, the diagnosis of chronic myeloid leukemia (CML) in females during the child bearing age is rare. In certain parts of the world, CML may be diagnosed at a much younger age than in the western countries. After the introduction of tyrosine kinase inhibitors (TKIs), patients with CML are enjoying long-term survival with an excellent quality of life comparable to that of healthy individuals, so younger female patients can become pregnant while receiving their CML treatment. We report a young female patient with CML and primary infertility who underwent in vitro fertilization (IVF) that lead to twin pregnancy. The patient received successful management for her pregnancy then optimal control of her CML at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia. Keywords: Chronic myeloid leukemia; Pregnancy; Tyrosine kinase inhibitors; Interferon; In- vitro-fertilization
Introduction OPEN ACCESS CML is a clonal myeloproliferative disease characterized by neoplastic proliferation of pluripotent myeloid stem cells and the Philadelphia chromosome which arises from the reciprocal *Correspondence: chromosomal translocation t 9,22 (q34,q11) [1-4]. CML is the third most common type of leukemia Khalid Ahmed Al-Anazi, Department of as it represents 15-20% of all adult leukemias [4,5]. The disease course consists of three phases: a Hematology and Hematopoietic Stem chronic phase, an accelerated phase and a blast cell crisis [5]. Cell Transplantation, Oncology Center, The advent of TKIs has revolutionized the management of patients with CML to the extent King Fahad Specialist Hospital, P.O. that the vast majority of patients can enjoy long-lasting clinical, hematological remissions and a Box: 15215, Dammam 31444, Saudi substantial proportion of them achieve molecular remissions of their previously fatal disease Arabia, Tel: 966 - 03- 8431111; Fax: 966 [6,7]. However, hematopoietic stem cell transplantation (HSCT) remains the only known curative -13- 8427420; therapeutic option [5,6]. E-mail: [email protected] Received Date: 28 Oct 2016 Case Presentation Accepted Date: 18 Nov 2016 A 24 year old Saudi lady was diagnosed to have CML at KFSH in Dammam on 03/05/2011. At Published Date: 24 Nov 2016 presentation, she was found to have splenomegaly of 2 centimeters below costal margin, but she had Citation: no palpable liver or external lymphadenopathy. Her complete blood count (CBC) showed white 9 AlSaffar WA, Abdulbaqi M, Jatham A, blood count (WBC): 117.2×10 /liter (L), hemoglobin (Hb): 12.7 gram/ deciliter (g/dL), platelets 9 Al-Anazi KA. Successful Management (PLT): 172×10 /L. Differential cell count showed 84.3% neutrophils. Peripheral blood film (PBF) of Twin Pregnancy via In Vitro revealed neutrophilia with band forms, myelocytes and metamyelocytes but no blast cells. Bone Fertilization in a Patient with Chronic marrow (BM) aspirate showed a dry tap, while trephine biopsy showed a hypercellular marrow consistent with chronic myeloproliferative neoplasm without significant fibrosis and less than 1% Myeloid Leukemia. J Hematol Mult blast cells. Cytogenetic analysis revealed the presence of Philadelphia chromosome and molecular Myeloma. 2016; 1(1): 1003. testing for BCR-ABL, p210 transcript by real time quantitative polymerase chain reaction (RQ- Copyright © 2016 Al-Anazi KA. This is PCR) was 71% on the international scale (IS) (Table 1). Ultrasound of abdomen and pelvis showed an open access article distributed under mild hepatosplenomegaly with features of fatty liver infiltration, but no evidence of internal the Creative Commons Attribution lymphadenopathy. Prior to the diagnosis of her CML, she was married for 5 years, but without License, which permits unrestricted offspring as she had primary infertility. After confirming the diagnosis of CML, the patient received use, distribution, and reproduction in cytoreductive therapy with hydroxyurea then she was commenced on imatinib 400 mg per day. any medium, provided the original work Thereafter, the patient had regular follow up at the outpatient clinic and herisease d was showing is properly cited. good response to imatinib as reflected by her clinical and laboratory profiles. For her infertility,
Remedy Publications LLC. 1 2016 | Volume 1 | Issue 1 | Article 1003 Al-Anazi KA, et al., Journal of Hematology & Multiple Myeloma
Table 1: BCR-ABL values during the course of the illness. Date BCR-ABL p210 on international scale May 2011 71 %
February 2012 7 %
June 2012 60 %
August 2012 100 %
April 2013 42.6 %
July 2013 5.2 %
June 2014 0.39 %
June 2015 0.089 %
February 2016 0.023 %
August 2016 0.003 % Figure 1: Bone marrow aspiration 15 months after the diagnosis of CML. It shows granulocytes at various stages of development, without excess of the patient was having follow up at a private institution and she blast cells. was undergoing ovarian stimulation. One year after the diagnosis of her CML, she underwent in vitro fertilization (IVF) at the private initial therapy should be in the form of TKIs, such as imatinib, which institution. After confirming pregnancy at KFSH in Dammam, have recently become the treatment of choice for CML [6,8]. The imatinib treatment was discontinued and the patient was commenced best method of monitoring the response of patients with CML to on pegylated recombinant interferon alpha therapy. The initial dose TKI therapy is by performing RQ-PCR for the BCR-ABL transcript of interferon was 60 microgram (mcg) per day subcutaneously and at three monthly intervals [8]. In case failure of imatinib therapy is it was doubled two weeks later, but due to encountering side effects, encountered, initiation of treatment with second generation TKIs the original dose was resumed. After finishing 3 months of interferon such as dasatinib and nilotinib is usually recommended [8]. therapy and entering the second trimester of her pregnancy, the patient was shifted back to imatinib on 28/08/2012. Meanwhile, A small proportion of female patients with CML are diagnosed there was an increase in BCR-ABL transcript to 100% on the IS, so a during the childbearing age as the median age at the diagnosis new BM biopsy was taken and it showed evidence of continued first of CML is in the sixth decade of life [9,10]. CML occurs in 10% of chronic phase (Figure 1). In December 2012 and during week 32 of pregnancy-associated leukemias [9,10]. The management of CML gestation, the patient underwent lower segment Cesarean section during pregnancy is a difficult task because of the potential adverse (LSCS) and the delivered male babies were 267 and 276 grams in effects of the treatment on both the mother and the fetus [11]. The weight so they were kept in the neonatology unit for 4 weeks before therapeutic approaches to CML diagnosed during pregnancy include their discharge. The mother was advised not to breast feed her newly supportive care including leukapheresis, cytotoxic chemotherapy born babies whilst receiving imatinib therapy. such as hydroxyurea, interferon-α and TKIs such as imatinib [9,10]. Despite the continuation of imatinib therapy after delivery, There are very few reports of successful outcome of pregnancy in the BCR-ABL transcript started to rise again from 42.6% to 60%. mothers having CML and receiving imatinib throughout pregnancy Clinically, there was no hepatosplenomegaly or external palpable [11]. Exposure to imatinib in early pregnancy has been associated lymphadenopathy. The blood indices remained normal and PBF with spontaneous abortion and a number of congenital abnormalities did not show any blast cells. A new BM biopsy was performed and it such as skeletal malformations in addition to renal, respiratory as showed that the disease was still in chronic phase. After encountering well as gastrointestinal defects [9,10,12]. There is no evidence that a imatinib failure that was most likely caused by treatment interruptions, brief exposure to imatinib therapy during pregnancy can adversely it was decided to shift the patient to dasatinib at 100mg/day in August affect the developing fetus [10,13]. However, female patients with 2012. Thereafter, the patient continued to have her regular follow up CML who wish to become pregnant should be advised to wait till and she remained clinically stable. Her blood counts remained within they have achieved sustained major molecular responses (MMRs) normal limits and the BCR-ABL decreased to 42.6% in April 2013 or better responses for at least two years [9,10,14]. Decisions on and 5.2% in July 2013 (Table 1). the interruption of TKI treatment and starting alternative therapies In June 2014, despite the further decrease in the BCR-ABL and planning delivery should all be made after making thorough transcript to 0.39% on the IS, the patient became intolerant to discussions with the patient, her family as well as obstetricians and dasatinib so she was shifted to nilotinib 400 mg twice daily. Thereafter, neonatologists [10]. the patient was continued on nilotinib and she remained stable from Dasatinib is an orally administered inhibitor of multiple kinases clinically and laboratory points of view and her BCR-ABL continued including BCR-ABL and SRC family kinases [15,16]. It is indicated to decrease further as shown in Table 1. The patient was last seen at for the treatment of: newly diagnosed CML in chronic phase, CML the outpatient clinic on 04/08/2016. She was totally asymptomatic in accelerated or blastic phase in addition to resistance or intolerance and her physical examination showed no abnormality. Her CBC to imatinib [15,16]. It has approximately 325 fold potency than showed WBC of 7.82×109/L, Hb of 11.8 g/dL and PLTs of 215×109/L imatinib [15-17]. It was approved for the treatment of CML in the with neutrophils of 4.7×109/L. She was continued on nilotinib and she year 2006 [18]. It has the following adverse effects: neutropenia, was given new follow up appointment in 3 months. thrombocytopenia, diarrhea, headache, fatigue, dyspnea and pleural Discussion effusions [16]. For adult patients who present with CML in chronic phase, the Nilotinib is a selective inhibitor of BCR-ABL and is more potent
Remedy Publications LLC. 2 2016 | Volume 1 | Issue 1 | Article 1003 Al-Anazi KA, et al., Journal of Hematology & Multiple Myeloma than imatinib as it has been shown to achieve deeper and earlier 3. Michallet M, Maloisel F, Delain M, Hellmann A, Rosas A, Silver RT, et al; molecular responses [14,19-21]. It is indicated for the treatment of: PEG-Intron CML Study Group. Pegylated recombinant interferon alpha- newly diagnosed CML in chronic phase and for the treatment of CML 2b vs recombinant interferon alpha-2b for the initial treatment of chronic- phase chronic myelogenous leukemia: a phase III study. Leukemia. 2004; after failure of imatinib or in case of intolerance to imatinib [4,20-22]. 18: 309-315. However, it has the following side effects: nausea, vomiting, diarrhea, constipation, pruritus, skin rash, BM suppression, increased lipases, 4. Jarkowski A, Sweeney RP. Nilotinib: a new tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Pharmacotherapy. 2008; hyperglycemia, prolongation of QT interval and sudden death [22]. 28: 1374-1382. Interferon-α inhibits cell proliferation by its effects on protein 5. Rochau U, Kluibenschaedl M, Stenehjem D, Kuan-Ling K, Radich J, synthesis, RNA degradation and possibly by modulation of the Oderda G, et al. Effectiveness and cost-effectiveness of sequential treatment immune system [12]. It does not inhibit DNA synthesis and due to of patients with chronic myeloid leukemia in the United States: a decision its high molecular weight it does not cross the placental barrier to a analysis. Leuk Res Treatment. 2015, Article ID 982395. significant degree [9,12]. Its use in pregnancy is generally safe and is 6. Gratwohl A, Pfirrmann M, Zander A, Kröger N, Beelen D, Novotny J, et al; not usually associated with congenital malformations or any other SAKK; German CML Study Group. Long-term outcome of patients with fetal adverse effects [9,12]. Hence, CML diagnosed during gestation newly diagnosed chronic myeloid leukemia: a randomized comparison of can preferably be treated with interferon-α throughout pregnancy stem cell transplantation with drug treatment. Leukemia. 2016; 30: 562- 569. without any apparent increase in adverse fetal outcome or congenital malformations [12]. However, due to the high rate of encountering 7. Saußele S, Richter J, Hochhaus A, Mahon FX. The concept of treatment- side effects, many pregnant ladies cannot tolerate interferon therapy free remission in chronic myeloid leukemia. Leukemia. 2016; 30: 1638- [12]. 1647. 8. Goldman JM. Initial treatment for patients with CML. Hematology Am Ideally female patients with CML belonging to the child bearing Soc Hematol Educ Program. 2009: 453-460. age who like to become pregnant should wait till they achieve at least MMR of their disease. Our patient was seeking gestation, as she had 9. Milojkovic D, Apperley JF. How I treat leukemia during pregnancy. Blood. 2014; 123: 974-984. been suffering from infertility, before achievement of optimal control of her CML. Dealing with pregnancy in an uncontrolled CML patient 10. Al-Anazi KA. Update on leukemia in pregnancy. In: Leukemias-updates was a real challenge to the treating team. The initial step was stopping and new insights. Guenova M, Balatzenko G, editors. In Tech. 2015. imatinib and shifting her to interferon till the end of the first trimester 11. Singhal M, Meena K, Bharadwaj N, Mundaliya R, Agarwal S. Successful of pregnancy so as to avoid the possible adverse effects of imatinib pregnancy outcome in a patient of chronic myeloid leukemia on imatinib on the developing embryos. After passing the stage of organogenesis, therapy. Int J Reprod Contracept Obstet Gynecol. 2016; 5: 913-915. she was resumed on imatinib then she was continued to have follow 12. Shapira T, Pereg D, Lishner M. How I treat acute and chronic leukemia in up on almost weekly basis during her pregnancy. After passing the pregnancy. Blood Rev. 2008; 22: 247-259. second trimester of her pregnancy and after prior arrangements with 13. Ault P, Kantarjian H, O'Brien S, Faderl S, Beran M, Rios MB, et al. the obstetricians, she had LSCS at week 32 of gestation. The healthy, Pregnancy among patients with chronic myeloid leukemia treated with but underweight baby boys, were kept under close supervision in the imatinib. J Clin Oncol. 2006; 24: 1204-1208. neonatology unit for almost four weeks. Their physical and laboratory 14. Usui N. Discontinuation of tyrosine kinase inhibitors and pregnancy for evaluations showed that they were healthy without congenital or female patients with chronic myeloid leukemia. J Hematol Transfus. 2014; other abnormalities. 2: 1023. After delivery, the focus shifted to controlling the mother's 15. McCormack PL, Keam SJ. Dasatinib: a review of its use in the treatment of CML. Initially, she was shifted to dasatinib after encountering chronic myeloid leukaemia and Philadelphia chromosome-positive acute imatinib failure. Thereafter, dasatinib made significant change in her lymphoblastic leukaemia. Drugs. 2011; 71: 1771-1795. management, but unfortunately she become intolerant to the drug, so 16. Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg the treating team to start her on nilotinib. The third TKI brought her SL, et al. Dasatinib induces durable cytogenetic responses in patients disease under more optimal control. with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008; 22: 1200-1206. Conclusion 17. Abbott BL. Dasatinib: from treatment of imatinib-resistant or -intolerant Young females with CML should wait till their disease is patients with chronic myeloid leukemia to treatment of patients with optimally controlled before becoming pregnant. 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